Imidazol derivatives as raf kinase inhibitors

ABSTRACT

Compounds of formula (I) wherein X is O, CH 2 , S or NH, or the moiety X—R 1  is hydrogen; V is CH or N; R 1  is hydrogen, C 1-6 -alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, heterocyclyl, heterocyclylC 1-6 alkyl, heteroaryl, or heteroarylC 1-6 alkyl any of which except for hydrogen may be optionally substituted; R 2  and R 3  independently represent optionally substituted C 1-6 -alkyl, or R 2  and R 3  together with the carbon atom to which they are attached form an optionally substituted C 3-7 cycloalkyl or C 3-7 cycloalkenyl ring; or R 2  and R 3  together with the carbon atom to which they are attached form an optionally substituted 5 to 7-membered heterocyclyl ring containing up to 3 heteroatoms selected from N, O, S.R 4  and R 5  independently represent hydrogen, C 1-6  alkyl, C 3-7 cycloalkyl, aryl, arylC 1-6 alkyl, heteroaryl, heteroarylC 1-6 alkyl, heterocyclyl, or heterocyclylC 1-6 alkyl, any of which except for hydrogen may be optionally substituted or R 4  and R 5  together with the nitrogen atom to which they are attached form 4- to 8-membered ring; Ar is an aryl or heteroaryl ring either of which may be optionally substituted; one of X 1  and X 2  is N and the other is NR 6 , wherein R 6  is hydrogen, C 1-6 alkyl, or arylC 1-6 alkyl or pharmaceutically acceptable salts thereof, their use as inhibitors of Raf kinases, and pharmaceutical compositions containing them.

[0001] This invention relates to novel compounds and their use aspharmaceuticals particularly as Raf kinase inhibitors for the treatmentof neurotraumatic diseases.

[0002] Raf protein kinases are key components of signal transductionpathways by which specific extracellular stimuli elicit precise cellularresponses in mammalian cells. Activated cell surface receptors activateras/rap proteins at the inner aspect of the plasmamembrane which in turnrecruit and activate Raf proteins. Activated Raf proteins phosphorylateand activate the intracellular protein kinases MEK1 and MEK2. In turn,activated MEKs catalyse phosphorylation and activation of p42/p44mitogen-activated protein kinase (MAPK). A variety of cytoplasmic andnuclear substrates of activated MAPK are known which directly orindirectly contribute to the cellular response to environmental change.Three distinct genes have been identified in mammals that encode Rafproteins; A-Raf, B-Raf and C-Raf (also known as Raf-1) and isoformicvariants that result from differential splicing of MRNA are known.

[0003] Inhibitors of Raf kinases have been suggested for use indisruption of tumor cell growth and hence in the treatment of cancers,e.g. histiocytic lymphoma, lung adenocarcinoma, small cell lung cancerand pancreatic and breast carcinoma; and also in the treatment and/orprophylaxis of disorders associated with neuronal degeneration resultingfrom ischemic events, including cerebral ischemia after cardiac arrest,stroke and multi-infarct dementia and also after cerebral ischemicevents such as those resulting from head injury, surgery and/or duringchildbirth.

[0004] We have now found a group of novel compounds that are inhibitorsof Raf lcinases, in particular inhibitors of B-Raf kinase.

[0005] According to the invention there is provided compounds of formula(I):

[0006] wherein

[0007] X is O, CH₂, S or NH, or the moiety X—R¹ is hydrogen;

[0008] V is CH or N;

[0009] R¹ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, arylC₁₋₆alkyl,heterocyclyl, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆alkylany of which, except for hydrogen, may be optionally substituted;

[0010] R² and R³ independently represent optionally substitutedC₁₋₆alkyl, or R² and R³ together with the carbon atom to which they areattached form an optionally substituted C₃₋₇cycloalkyl orC₃₋₇cycloalkenyl ring; or R² and R³ together with the carbon atom towhich they are attached form an optionally substituted 5 to 7-memberedheterocyclyl ring containing up to 3 heteroatoms selected from N, O, S.

[0011] R⁴ and R⁵ independently represent hydrogen, C₁₋₆alkyl,C₃₋₇cycloalkyl, aryl, arylC₁₋₆alkyl, heteroaryl, heteroarylC₁₋₆alkyl,heterocyclyl, or heterocyclylC₁₋₆alkyl, any of which, except forhydrogen, may be optionally substituted or R⁴ and R⁵ together with thenitrogen atom to which they are attached form 4- to 8-membered ring;

[0012] Ar is an aryl or heteroaryl ring either of which may beoptionally substituted;

[0013] one of X₁ and X₂ is N and the other is NR⁶, wherein R⁶ ishydrogen, C₁₋₆alkyl, or arylC₁₋₆alkyl;

[0014] or pharmaceutically acceptable salts thereof.

[0015] As used herein, the double bond indicated by the dotted lines offormula (I), represent the possible tautomeric ring forms of thecompounds falling within the scope of this invention, the double bondbeing to the unsubstituted nitrogen atom.

[0016] Alkyl and alkenyl groups referred to herein, individually or aspart of larger groups e.g. alkoxy, may be straight or branched groupscontaining up to six carbon atoms and are optionally substituted by oneor more groups selected from the group consisting of aryl, heteroaryl,heterocyclyl, C₁₋₆alkoxy, C₁₋₆alkylthio, arylC₁₋₆alkoxy,arylC₁₋₆alkylthio, amino, mono- or di-C₁₋₆alkylamino, cycloalkyl,cycloalkenyl, carboxy and esters thereof, amide, sulphonamido, ureido,guanidino, C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino, C1-6acyloxy,azido, hydroxy, hydroxyimino and halogen. Preferably the optionalsubstituent contains a solubilising group; suitable solubilisingmoieties will be apparent to those skilled in the art and includehydroxy and amine groups. Even more preferably the optional substituentinclude heterocyclyl, amino, mono- or di-C₁₋₆alkylamino, amide, andhydroxy or any combination thereof.

[0017] Cycloalkyl and cycloalkenyl groups referred to herein includegroups having from three to seven ring carbon atoms and are optionallysubstituted as described hereinabove for alkyl and alkenyl groups.

[0018] When used herein, the term “aryl” includes, unless otherwisedefined, single and fused rings suitably containing from 4 to 7,preferably 5 or 6, ring atoms in each ring, which rings, may each beunsubstituted or substituted by, for example, up to three substituents.

[0019] Suitable aryl groups include phenyl and naphthyl such as1-naphthyl or 2-naphthyl.

[0020] When used herein the term “heterocyclyl” includes, unlessotherwise defined, non-aromatic, single and fused, rings suitablycontaining up to four heteroatoms in each ring, each of which isselected from O, N and S, which rings, may be unsubstituted orsubstituted by, for example, up to three substituents. Each heterocyclicring suitably has from 4 to 7, preferably 5 or 6, ring atoms. A fusedheterocyclic ring system may include carbocyclic rings and need includeonly one heterocyclic ring. Examples of heterocyclyl groups includepyrrolidine, piperidine, piperazine, morpholine, imidazolidine andpyrazolidine.

[0021] When used herein, the term “heteroaryl” includes, unlessotherwise defined, mono- and bicyclic heteroaromatic ring systemscomprising up to four, preferably 1 or 2, heteroatoms each selected fromO, N and S. Each ring may have from 4 to 7, preferably 5 or 6, ringatoms. A bicyclic heteroaromatic ring system may include a carbocyclicring. Examples of heteroaryl groups include pyrrole, quinoline,isoquinoline, pyridine, pyrimidine, oxazole, thiazole, thiadiazole,triazole, imidazole and benzimidazole.

[0022] Aryl, hererocyclyl and heteroaryl groups may be optionallysubstituted by preferably up to three substituents. Suitablesubstituents include halogen, C₁₋₆alkyl, aryl, aryl C₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxy C₁₋₆alkyl, halo C₁₋₆alkyl, arylC₁₋₆alkoxy,hydroxy, nitro, cyano, azido, amino, mono- and di-N-C₁₋₆alkylamino,acylamino, arylcarbonylamino, acyloxy, carboxy, carboxy salts, carboxyesters, carbamoyl, mono- and di-N-C₁₋₆alkylcarbamoyl,C₁₋₆-alkoxycarbonyl, aryloxycarbonyl, ureido, guanidino,C₁₋₆alkylguanidino, amidino, C₁₋₆alkylamidino, sulphonylamino,aminosulphonyl, C₁₋₆alkylthio, C₁₋₆alkylsulphinyl, C₁₋₄alkylsulphonyl,heterocyclyl, heteroaryl, heterocyclyl C₁₋₆alkyl, hydroxyimino-C₁₋₆alkyland heteroaryl C₁₋₆alkyl. Preferably the optional substituent contains asolubilising group; suitable solubilising moieties will be apparent tothose skilled in the art and include hydroxy and amine groups. Even morepreferably the optional substituent include heterocyclyl, amino, mono-or di-C₁₋₆alkylamino, amide, and hydroxy or any combination thereof.

[0023] X is preferably NH or X—R¹ is hydrogen and when X is NH, R¹ ispreferably C₁₋₆alkyl or hydrogen.

[0024] When V is CH, X—R¹ is preferably hydrogen.

[0025] When V is N, X—R¹ is preferably NH₂.

[0026] Most preferably X—R¹ is hydrogen.

[0027] Ar is preferably an optionally substituted phenyl.

[0028] Preferred substituents for the group Ar include halo, hydroxy,hydroxy C₁₋₆alkyl, e.g. hydroxymethyl, hydroxyimino-C₁₋₆alkyl andC₁₋₆alkoxy e.g. methoxy, more preferred are halo and hydroxy. When Ar isphenyl the substituents are preferably present in the 3-position or the3,4-positions. When Ar is phenyl it preferably has a 3-hydroxysubstituent. Particular substitution patterns for Ar when phenyl are3-hydroxy, 3-hydroxy-4-halo e.g. 3-hydroxy-4-chloro or3-hydroxy-4-bromo, 3-hydroxy-4-methyl and 3-hydroxy-4-methoxy, moreparticularly 3-hydroxy-4-chloro.

[0029] R² and R³ independently represent C₁₋₆alkyl or R² and R³ togetherwith the carbon atom to which they are attached form an optionallysubstituted C₃₋₇cycloalkyl or C₃₋₇cycloalkyl ring. Alternatively R² andR³ together with the carbon atom to which they are attached form anoptionally substituted 5 to 7-membered heterocyclyl ring containing upto 3 heteroatoms selected from N, O and S.

[0030] R² and R³ preferably independently represent optionallysubstituted C₁₋₆alkyl, or R² and R³ together with the carbon atom towhich they are attached form an optionally substituted C₃₋₇cycloalkyl orC₅₋₇cycloalkenyl ring. More preferably R² and R³ represent C₁₋₆alkyl, orR² and R³ together with the carbon atom to which they are attached forman optionally substituted C₃₋₇cycloalkyl ring. In particular R² and R³represent methyl

[0031] Preferably R⁴ and R⁵ are independently hydrogen, C₁₋₆alkyl,arylC₁₋₆alkyl, C₃₋₇cycloalkyl any of which except hydrogen may beoptionally substituted or R⁴ and R⁵ together with the nitrogen to whichthey are attached from an optionally substituted 5 or 6 membered ringoptionally containing up to 2 heteroatoms selected from N or O, forexample morpholine, pyrrolidine or piperazine.

[0032] The compounds of formula (I) preferably have a molecular weightof less than 800.

[0033] Particular compounds according to the invention include thosementioned in the examples and their pharmaceutically acceptable salts.It will be understood that the invention includes pharmaceuticallyacceptable derivatives of compounds of formula (I) and that these areincluded within the scope of the invention.

[0034] As used herein “pharmaceutically acceptable derivative” includesany pharmaceutically acceptable salt, ester or salt of such ester of acompound of formula (I) which, upon administration to the recipient, iscapable of providing (directly or indirectly) a compound of formula (I)or an active metabolite or residue thereof.

[0035] It will be appreciated that for use in medicine the salts of thecompounds of formula (I) should be pharmaceutically acceptable. Suitablepharmaceutically acceptable salts will be apparent to those skilled inthe art and include those described in J. Pharm. Sci., 1977, 66, 1-19,such as acid addition salts formed with inorganic acids e.g.hydrochloric, hydrobromic, sulfuric, nitric or phosphoric acid; andorganic acids e.g. succinic, maleic, acetic, fumaric, citric, tartaric,benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid.Other salts e.g. oxalates, may be used, for example in the isolation ofcompounds of formula (I) and are included within the scope of thisinvention.

[0036] The compounds of this invention may be in crystalline ornon-crystalline form, and, if crystalline, may optionally be hydrated orsolvated. This invention includes within its scope stoichiometrichydrates as well as compounds containing variable amounts of water.

[0037] The invention extends to all isomeric forms includingstereoisomers and geometric isomers of the compounds of formula (I)including enantiomers and mixtures thereof e.g. racemates. The differentisomeric forms may be separated or resolved one from the other byconventional methods, or any given isomer may be obtained byconventional synthetic methods or by stereospecific or asymmetricsyntheses.

[0038] Since the compounds of formula (I) are intended for use inpharmaceutical compositions it will readily be understood that they areeach preferably provided in substantially pure form, for example atleast 60% pure, more suitably at least 75% pure and preferably at least85%, especially at least 98% pure.(% are on a weight for weight basis).Impure preparations of the compounds may be used for preparing the morepure forms used in the pharmaceutical compositions.

[0039] Compounds of formula (I) are imidazole derivatives which may bereadily prepared using procedures well-known to those skilled in theart, and described in, for instance, Comprehensive HeterocyclicChemistry, Editors Katritzky and Rees, Pergamon Press, 1984, 5, 457-497,from starting materials which are either commercially available or canbe prepared from such by analogy with well-known processes. A key stepin many such syntheses is the formation of the central imidazolenucleus. Suitable procedures are described in inter alia U.S. Pat. Nos.3,707,475 and 3,940,486 which are herein incorporated by reference intheir entirety. These patents describe the synthesis of α-diketones andα-hydroxyketones (benzoins) and their subsequent use in preparingimidazoles and N-hydroxyl imidazoles.

[0040] Preferred methods for preparing compounds of this invention areas outlined in the above scheme, wherein Y₁ is COOH or a C₁₋₆ alkyl orarylC₁₋₆alkyl ester thereof. α-Diketones are prepared by condensation ofthe anion of, for example, a 4-substituted pyridine derivative (V=CH,R¹−X=H) with the Weinreb amide of an aryl acid or an aryl-aldehyde,followed by oxidation of the intermediate product. Heating the diketonewith an aldehyde and ammonium acetate in acetic acid allows access tothe imidazole nucleus. Thereafter, the group Y₁ may be converted into agroup Y using conventional functional group interconversion procedures.Functional group transformations are well known in the art and aredescribed in, for instance, Comprehensive Organic Functional GroupTransformations, eds. A. R. Katritzky, O. Meth-Cohn, and C. W. Rees(Elsevier Science Ltd., Oxford, 1995), Comprehensive Organic Chemistry,eds. D. Barton and W. D. Ollis (Pergamon Press, Oxford, 1979), andComprehensive Organic Transformations, R. C. Larock (VCH PublishersInc., New York, 1989). The group Y₁ is preferably COOCH₃.

[0041] Non-selective alkylation of the imidazole nitrogen (using one ofthe procedures outlined in N. J. Liverton et at; J. Med. Chem., 1999,42, 2180-2190) with a compound of formula L—R⁶ wherein L is a leavinggroup, e.g. halo, sulfonate or triflate, will yield both isomers of thecompounds of formula (I) where X₁ or X₂ is NR⁶ in which R⁶ is other thanhydrogen, the isomers can be separated by chromatographic methods.

[0042] During the synthesis of the compounds of formula (I) labilefunctional groups in the intermediate compounds, e.g. hydroxy, carboxyand amino groups, may be protected. A comprehensive discussion of theways in which various labile functional groups may be protected andmethods for cleaving the resulting protected derivatives is given in forexample Protective Groups in Organic Chemistry, T. W. Greene and P. G.M. Wuts, (Wiley-Interscience, New York, 2nd edition, 1991).

[0043] The compounds of formula (I) may be prepared singly or ascompound libraries comprising at least 2, for example 5 to 1,000compounds, and more preferably 10 to 100 compounds of formula (I).Libraries of compounds of formula (I) may be prepared by a combinatorial‘split and mix’ approach or by multiple parallel synthesis using eithersolution phase or solid phase chemistry, by procedures known to thoseskilled in the art.

[0044] Thus according to a further aspect of the invention there isprovided a compound library comprising at least 2 compounds of formula(I), or pharmaceutically acceptable salts thereof.

[0045] Pharmaceutically acceptable salts may be prepared conventionallyby reaction with the appropriate acid or acid derivative.

[0046] The novel carboxylic esters and the corresponding acids offormula (II) which are used as intermediates in the synthesis of thecompounds of formula (I) also form part of the present invention:

[0047] wherein X, V, R¹, R², R³, Ar, X₁ and X₂ are as defined forformula (I) and R is hydrogen, C₁₋₆alkyl or arylC₁₋₆alkyl.

[0048] As indicated above the compounds of formula (I) and theirpharmaceutically acceptable salts are useful for the treatment and/orprophylaxis of disorders in which Raf kinases, in particular B-Rafkinase, are implicated.

[0049] According to a further aspect of the invention there is providedthe use of a compound of formula (I) or a pharmaceutically acceptablesalt thereof as an inhibitor of B-Raf kinase.

[0050] As indicated above the compounds of formula (I) and theirpharmaceutically acceptable salts are useful the treatment and/orprophylaxis of disorders associated with neuronal degeneration resultingfrom ischemic events.

[0051] According to a further aspect of the invention there is provideda method of treatment or prophylaxis of a neurotraumatic disease, in amammal in need thereof, which comprises administering to said mammal aneffective amount of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof.

[0052] According to a further aspect of the invention there is providedthe use of a compound of formula (I) or a pharmaceutically acceptablesalt thereof in the manufacture of a medicament for the prophylactic ortherapeutic treatment of any disease state in a human, or other mammal,which is exacerbated or caused by a neurotraumatic event.

[0053] Neurotraumatic diseases/events as defined herein include bothopen or penetrating head trauma, such as caused by surgery, or a closedhead trauma injury, such as caused by an injury to the head region. Alsoincluded within this definition is ischemic stroke, particularly to thebrain area, transient ischemic attacks following coronary by-pass andcognitive decline following other transient ischemic conditions.

[0054] Ischemic stroke may be defined as a focal neurologic disorderthat results from insufficient blood supply to a particular brain area,usually as a consequence of an embolus, thrombi, or local atheromatousclosure of the blood vessel. Roles for stress stimuli (such as anoxia),redox injury, excessive neuronal excitatory stimulation and inflammatorycytokines in this area has been emerging and the present inventionprovides a means for the potential treatment of these injuries.Relatively little treatment, for an acute injury such as these has beenavailable.

[0055] The compounds of the invention may also be used in the treatmentor prophylaxis of cancers.

[0056] The compounds of the invention may also be of use for thetreatment or prophylaxis of CSBP/p38 mediated diseases as described inWO 99/01131 and WO 99/01130.

[0057] It will be appreciated by those skilled in the art that referenceherein to treatment extends to prophylaxis as well as the treatment ofestablished infections or symptoms.

[0058] In order to use the compounds of formula (I) in therapy, theywill normally be formulated into a pharmaceutical composition inaccordance with standard pharmaceutical practice.

[0059] According to a further aspect of the invention there is provideda pharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.

[0060] The compounds of formula (I) may conveniently be administered byany of the routes conventionally used for drug administration, forinstance, parenterally, orally, topically or by inhalation. Thecompounds of formula (I) may be administered in conventional dosageforms prepared by combining it with standard pharmaceutical carriersaccording to conventional procedures. The compounds of formula (I) mayalso be administered in conventional dosages in combination with aknown, second therapeutically active compound. These procedures mayinvolve mixing, granulating and compressing or dissolving theingredients as appropriate to the desired preparation. It will beappreciated that the form and character of the pharmaceuticallyacceptable carrier is dictated by the amount of compound of formula (I)with which it is to be combined, the route of administration and otherwell-known variables. The carrier(s) must be “acceptable” in the senseof being compatible with the other ingredients of the formulation andnot deleterious to the recipient thereof.

[0061] The pharmaceutical carrier employed may be, for example, either asolid or liquid. Exemplary of solid carriers are lactose, terra alba,sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate,stearic acid and the like. Exemplary of liquid carriers are syrup,peanut oil, olive oil, water and the like. Similarly, the carrier ordiluent may include time delay material well known to the art, such asglyceryl mono-stearate or glyceryl distearate alone or with a wax.

[0062] A wide variety of pharmaceutical forms can be employed. Thus, ifa solid carrier is used, the preparation can be tableted, placed in ahard gelatin capsule in powder or pellet form or in the form of a trocheor lozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 g. When a liquid carrier is used,the preparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule or nonaqueousliquid suspension.

[0063] The compounds of formula (I) are preferably administeredparenterally, that is by intravenous, intramuscular, subcutaneousintranasal, intrarectal, intravaginal or intraperitoneal administration.The intravenous form of parenteral administration is generallypreferred. The compounds may be administered as a bolus or continuousinfusion e.g. over 3 days. Appropriate dosage forms for suchadministration may be prepared by conventional techniques.

[0064] The compounds of formula (I) may also be administered orally.Appropriate dosage forms for such administration may be prepared byconventional techniques.

[0065] The compounds of formula (I) may also be administered byinhalation, that is by intranasal and oral inhalation administration.Appropriate dosage forms for such administration, such as aerosolformulations, may be prepared by conventional techniques.

[0066] The compounds of formula (I) may also be administered topically,that is by non-systemic administration. This includes the application ofthe inhibitors externally to the epidermis or the buccal cavity and theinstillation of such a compound into the ear, eye and nose, such thatthe compound does not significantly enter the blood stream.

[0067] For all methods of use disclosed herein the daily oral dosageregimen will preferably be from about 0.1 to about 80 mg/kg of totalbody weight, preferably from about 0.2 to 30 mg/kg, more preferably fromabout 0.5mg to 15 mg. The daily parenteral dosage regimen about 0.1 toabout 80 mg/kg of total body weight, preferably from about 0.2 to about30 mg/kg, and more preferably from about 0.5 mg to 15mg/kg. The dailytopical dosage regimen will preferably be from 0.1 mg to 150 mg,administered one to four, preferably two or three times daily. The dailyinhalation dosage regimen will preferably be from about 0.01 mg/kg toabout 1 mg/kg per day. It will also be recognized by one of skill in theart that the optimal quantity and spacing of individual dosages of theinhibitors will be determined by the nature and extent of the conditionbeing treated, the form, route and site of administration, and theparticular patient being treated, and that such optimums can bedetermined by conventional techniques. It will also be appreciated byone of skill in the art that the optimal course of treatment, i.e., thenumber of doses of the inhibitors given per day for a defined number ofdays, can be ascertained by those skilled in the art using conventionalcourse of treatment determination tests. In the case of pharmaceuticallyacceptable salts the above figures are calculated as the parent compoundof formula (I).

[0068] No toxicological effects are indicated/expected when a compoundof formula (I) is administered in the above mentioned dosage range.

[0069] All publications, including but not limited to patents and patentapplications, cited in this specification are herein incorporated byreference as if each individual publication were specifically andindividually indicated to be incorporated by reference herein as thoughfully set forth.

[0070] The following Examples illustrate the preparation ofpharmacologically active compounds of the invention and the followingDescriptions illustrate the preparation of intermediates used in thepreparation of these compounds.

[0071] Abbreviations used herein are as follows—THF meanstetrahydrofuran.

[0072] Description 1:2-[4-(4-Chloro-3-methoxyphenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methylpropionic acid methyl ester

[0073] Step 1. 4-Chloro-3,N-dimethoxy-N-methyl-benzamide

[0074] A suspension of 4-chloro-3-methoxybenzoic acid (F. Claudi et alJ. Med. Chem., 1992, 35, 4408) (37.2 g, 0.2 mol) in dichloromethane (500ml) containing oxalyl chloride (26 ml) was treated withN,N-dimethylformamide (10 drops). After stirring at room temperature for6 hours the solution was concentrated at reduced pressure, additionaldichloromethane was added to the residue and the solvent wasre-evaporated. The residue was dissolved in acetonitrile (600 ml) andmethoxymethylamine hydrochloride (20.5 g, 0.21 mol) added. The mixturewas cooled in an ice-bath, a solution of pyridine (80 ml) inacetonitrile (150 ml) added dropwise, and the mixture stirred at roomtemperature for 18 hours. The solution was concentrated and the residuepartitioned between ethyl acetate and saturated potassium carbonatesolution. The organic layer was separated, washed with brine, dried(MgSO₄) and concentrated at reduced pressure to give the title compound(40.0 g, 87%) as a colourless oil; MS(ES+) m/e 230/232 [M+H]⁺.

[0075] Step 2. 1-(4-Chloro-3-methoxy-phenyl)-2-pyridin-4-yl-ethanone

[0076] 4-Picoline (16.9 ml, 0.174 mol) was added dropwise to a stirredsolution of lithium di-isopropylamide (110 ml, 0.22 mol, 2M solution inheptane, ethylbenzene, tetrahydrofuran) in dry tetrahydrofuran (150 ml)at −78° C. After stirring at −78° C. for 15 minutes a solution of theproduct of Step 1 (40.0 g, 0.174 mol) in tetrahydrofuran (100 ml) wasadded dropwise. The reaction was allowed to warm to room temperatureover 3 hours. The solution was cooled in ice and saturated ammoniumchloride solution was added. The aqueous mixture was extracted withethyl acetate, washed with brine, dried (MgSO₄), filtered andconcentrated at reduced pressure. The resulting gum was triturated withcold diethyl ether/hexane (1:1, 300ml) and the solid collected to givethe title compound, as a pale yellow solid (29 g, 64%); MS(ES+) m/e262/264 [M+H]⁺.

[0077] Step 3.1-(4-Chloro-3-methoxy-phenyl)-2-pyridin-4-yl)-ethane-1,2-dione

[0078] A solution of the product of Step 2 (22.5 g, 86 mmol) indimethylsulphoxide (150 ml) was stirred at 55° C. Hydrogen bromide (48%aqueous, 21 ml) was added dropwise and the solution maintained at 55° C.for 1 hour. After cooling to room temperature, the solution was pouredinto a solution of sodium acetate (21 g) in ice-water (1 litre) and theresulting slurry was stirred at room temperature for 30 minutes. Themixture was extracted with ethyl acetate and the organic layers werecombined, washed with brine, dried (MgSO₄), filtered and concentrated atreduced pressure. The residue was triturated with diethyl ether/hexane(1:4) and the solid collected to give the title compound as a yellowsolid; MS(EI) m/e 275/277 [M]⁺.

[0079] Step 4.2-[4-(4-Chloro-3-methoxyphenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methylpropionic acid methyl ester

[0080] The product of Step 3 (11.03 g, 40 mmol),2,2-dimethyl-3-oxo-propionic acid methyl ester (6.77 g, 52 mmol) andammonium acetate (30.8 g, 400 mmol) were heated at 100° C. in aceticacid (100 ml) for 1 hour. The solution was concentrated under reducedpressure and the residue poured on to ice:0.880 ammonia solution. Thesolution was extracted with ethyl acetate, washed with water and brine,dried (MgSO₄) and evaporated to a solid. The solid was triturated withhexane, filtered and dried to afford the title compound (11.02 g, 71%)as a tan solid; MS(AP+) m/e 386/388[M+H]⁺.

[0081] Description 2:2-[4-(4-Chloro-3-methoxyphenyl)-5-pyridin-4-yl-1H-imidazole-2-yl]-2-methyl-propionicacid

[0082] The product of D1 (11.03 g, 28 mmol) was suspended in methanol(150 ml), 2M sodium hydroxide solution (42 ml, 84mmol) added and themixture warmed to 50° C. for 3 hours. After concentration at reducedpressure, the residue was dissolved in water, washed with ethyl acetateand then acidified to pH 4-5 with acetic acid. The resulting whiteprecipitate was filtered, washed with water and dried over phosphorouspentoxide at reduced pressure to afford the title compound (7.75 g, 74%)as a lemon solid; MS(AP+) m/e 372/374 [M+H]⁺.

[0083] Description 3:2-[4-(3,4-Dichlorophenyl)-5-pryidin-4-yl-1H-imidazole-2-yl]-2-methyl-propionicacid

[0084] Step 1. 1-(3,4-Dichlorophenyl)-2-pyridin-4-yl-ethane-1,2-diol

[0085] 4-(tert-Butyldimethylsilyloxymethyl)-pyridine (T. F. Gallagher etal, Bioorganic and Medicinal Chemistry; 1997, 5, 49) (67 g, 0.3mol) wasdissolved in THF (250 ml) and cooled to −40° C. The solution was treatedwith a 2M solution of lithuim diusopropylamide in THF (200 ml, 0.4 mol)and stirred for 45 minutes maintaining a temperature of −40 to −20° C.,before the dropwise addition of 3,4-dichlorobenzaldehyde (55.13 g, 0.32mol) in THF (250 ml). The mixture was allowed to warm to roomtemperature then stirred for a further 18 hours. After re-cooling to 0°C. the reaction was quenched with saturated ammonium chloride solution(500 ml), and the resulting two phase mixture separated. The aqueousphase was extracted with ethyl acetate and the combined organicsconcentrated under reduced pressure. The residue was dissolved in ethylacetate, washed with saturated sodium bicarbonate solution, water andbrine, dried (MgSO₄) and concentrated under reduced pressure to an oil(129 g). The oil was dissolved in THF (300 ml) and a 1M solution oftetrabutylammonium fluoride (360 ml, 0.36 mol) added dropwise. Thesolution was stirred at room temperature for 45 minutes, thenconcentrated to an oil under reduced pressure. The oil was dissolved inethyl acetate and washed with saturated sodium bicarbonate solution,water and brine, dried (MgSO₄) and evaporated under reduced pressure.The oil was triturated with hexane and the resulting solid filtered andwashed with hexane to afford the title compound (67.58 g 79%) as a tansolid; MS(AP+) m/e 284/286/288 [M+H]⁺.

[0086] Step 2. 1-(3,4-Dichlorophenyl)-2-pyridin-4-yl-ethane-1,2-dione

[0087] Dimethylsulfoxide (37 ml, 0.53 mol) was dissolved indichloromethane (250 ml) and cooled to −78° C. Oxalyl chloride (34.5 ml,0.40 mol) was added dropwise and the solution stirred for 20 min. Asolution of the product of Step 1 (34 g, 0.12 mol) in dimethylsulfoxide(40 ml) and dichloromethane (200 ml) was added dropwise at −78° C., andthe solution stirred for 30 minutes. Triethylamine (104 ml, 0.74 mol)was added dropwise and the solution became floculent such that overheadstirring became necessary. The solution was allowed to stir at roomtemperature over 2 hours then was poured on to ice/saturated sodiumbicarbonate solution. The aqueous layer was separated, and re-extractedwith dichloromethane. The combined organic phases were concentratedunder reduced pressure to a green-yellow solid. The solid wasredissolved in dichloromethane and washed with water and brine, dried(MgSO₄) and evaporated to a solid. The crude solid was purified bysilica gel chromatography eluting with dichloromethane, to afford thetitle compound (28.66 g, 85%) as a yellow solid; MS(−ve ion) m/e279/281/283 [M−H]⁻.

[0088] Step 3.2-[4-(3,4-Dichlorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methylpropionic acid methyl ester

[0089] The product of Step 2 (5.60 g, 20 mmol) was reacted with2,2-dimethyl-3-oxo-propionic acid methyl ester (3.38 g, 26 mmol) andammonium acetate (15.4 g, 200 mmol) as described in Description 1, Step4 to afford the title compound (5.06 g, 65%) as a tan solid; MS(AP+) m/e391/393/395 [M+H]⁺.

[0090] Step4.2-[4-(3,4-Dichlorophenyl)-5-pryidin-4-yl-1H-imidazole-2-yl]-2-methyl-propionicacid

[0091] The product of Step 3 (5.26 g, 14 mmol) was reacted with 2Msodium hydroxide solution (20 ml, 40 mmol) in methanol as described inDescription 2, to afford the title compound (2.36 g, 45%) as a beigesolid; MS(AP+) m/e 376/378/380 [M+H]⁺.

EXAMPLE 1 n-Butyl-2-[4-(4-chloro-3-methoxyphenyl)-5-pyridin-4-yl-1H-imidazole-2-yl]isobutylamide

[0092] 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (63mg, 0.33 mmol) and 1-hydroxybenzotriazole hydrate (41 mg, 0.3 mmol) wereadded to a suspension of the product of Description 2 (111 mg, 0.3 mmol)in dichloromethane (5 ml). The mixture was stirred at room temperatureuntil a clear yellow solution was obtained then n-butylamine (0.022 ml,0.3 mmol) added. The solution was stirred at room temperature overnightthen evaporated under reduced pressure to a solid. The solid wasdissolved in ethyl acetate, washed with saturated sodium bicarbonatesolution, water and brine, dried (MgSO₄) and evaporated under reducedpressure to afford the title compound (113 mg, 88%) as a cream solid;MS(AP−) m/e 425/427 [M−H]⁻.

EXAMPLE 2n-Butyl-2-[4-(4-chloro-3-hydroxyphenyl)-5-pyridin-4-yl-1H-imidazole-2-yl]isobutylamide

[0093] The product of Example 1 (130 mg, 0.3 mmol) was dissolved indichloromethane (5 ml) cooled to 0° C., then treated dropwise with 1Msolution of boron tribromide in dichloromethane (1.2 ml, 1.2 mmol).After stirring at room temperature for 18 hours, the heterogeneousmixture was diluted with dichloromethane (10 ml), 2M hydrochloric acid(1 ml) added and the mixture heated at reflux for 30 min. After coolingto room temperature, the solution was basified with saturated sodiumbicarbonate solution and extracted with dichloromethane. The combinedorganic extracts were washed with water and brine, dried (MgSO₄) andevaporated under reduced pressure to afford the title compound (101 mg,82%) as yellow powder; MS(AP−) m/e 411/413 [M−H]⁻.

EXAMPLE 32-[4-(3,4-Dichlorophenyl)-5-pyridin-4-yl-1H-imidazol-2-yl]-2-methyl-1-morpholin-4-yl-propan-1-one

[0094] The product of Description 3 (113 mg, 0.3 mmol) was reacted withmorpholine (0.027 ml, 0.3 mmol) as described in Example 1 to afford thetitle compound (66 mg, 49%) as a cream solid; MS(AP+) mr/e 445/447/449[M+H]⁺.

[0095] The following examples were prepared from the product ofDescription 2 by the general method described in Example 1. ExampleAmine Characterisation 4 2-[4-(4-Chloro-3-methoxy-phenyl)-5-pyridin-4-Pyrrolidine MS(AP+) m/e yl-1H-imidazol-2-yl]-2-methyl-1-pyrrolidin-1-426/428 [M + H]⁺ yl-propan-1-one 52-[4-(4-Chloro-3-methoxy-phenyl)-5-pyridin-4- Tetrahydro MS(AP+) m/eyl-1H-imidazol-2-yl]-N-(tetrahydro-furan-2- furfurylamine 455/457 [M +H]⁺ ylmethyl)-isobutyramide 62-[4-(4-Chloro-3-methoxy-phenyl)-5-pyridin-4- N-methyl- MS(AP+) m/eyl-1H-imidazol-2-yl]-2-methyl-1-(4-methyl- piperazine 454/456 [M + H]⁺piperazin-1-yl)-propan-1-one 7 N-(2-Acetylamino-ethyl)-2-[4-(4-chloro-3-N-acetyl ethylene MS(AP+) m/emethoxy-phenyl)-5-pyridin-4-yl-1H-imidazol-2- diamine 455/457 [M + H]⁺yl]-isobutyramide 8 2-[4-(4-Chloro-3-methoxy-phenyl)-5-pyridin-4-3-(Aminomethyl) MS(AP+) m/e yl-1H-imidazol-2-yl]-N-pyridin-3-ylmethyl-pyridine 462/464 [M + H]⁺ isobutyramide 92-[4-(4-Chloro-3-methoxy-phenyl)-5-pyridin-4- Cyclopropylamine MS(AP+)m/e yl-1H-imidazol-2-yl]-N-cyclopropyl- 411/413 [M + H]⁺ isobutyramide10 2-[4-(4-Chloro-3-methoxy-phenyl)-5-pyridin-4- 2-Methoxy MS(AP+) m/eyl-1H-imidazol-2-yl]-N-(2-methoxy-ethyl)- ethylamine 429/431 [M + H]⁺isobutyramide

[0096] The following examples were prepared by the general methoddescribed in Example 2. Example Precursor Characterisation 112-[4-(4-Chloro-3-hydroxy-phenyl)-5-pyridin-4- Example 4 MS(AP+) m/eyl-1H-imidazol-2-yl]-2-methyl-1-pyrrolidin-1- 412/414 [M + H]⁺yl-propan-1-one 12 2-[4-(4-Chloro-3-hydroxy-phenyl)-5-pyridin-4- Example5 MS(AP+) m/e yl-1H-imidazol-2-yl]-N-(tetrahydro-furan-2- 441/443 [M +H]⁺ ylmethyl)-isobutyramide 132-[4-(4-Chloro-3-hydroxy-phenyl)-5-pyridin-4- Example 6 MS(AP+) m/eyl-1H-imidazol-2-yl]-2-methyl-1-(4-methyl- 440/442 [M + H]⁺piperazin-1-yl)-propan-1-one 14N-(2-Acetylamino-ethyl)-2-[4-(4-chloro-3- Example 7 MS(AP+) m/ehydroxy-phenyl)-5-pyridin-4-yl-1H-imidazol-2- 441/443 [M + H]⁺yl]-isobutyramide 15 2-[4-(4-Chloro-3-hydroxy-phenyl)-5-pyridin-4-Example 8 MS(AP+) m/e yl-1H-imidazol-2-yl]-N-pyridin-3-ylmethyl- 448/450[M + H]⁺ isobutyramide 16 2-[4-(4-Chloro-3-hydroxy-phenyl)-5-pyridin-4-Example 9 MS(AP+) m/e yl-1H-imidazol-2-yl]-N-cyclopropyl- 397/399 [M +H]⁺ isobutyramide 17 2-[4-(4-Chloro-3-hydroxy-phenyl)-5-pyridin-4-Example 10 MS(AP+) m/e yl-1H-imidazol-2-yl]-N-(2-methoxy-ethyl)- 415/417[M + H]⁺ isobutyramide

[0097] It is to be understood that the present invention covers allcombinations of particular and preferred sub groups describedhereinabove.

BIOLOGICAL EXAMPLES

[0098] The activity of compounds of formula (I) as B-Raf inhibitors maybe determined by the following in vitro assay:

[0099] Raf Kinase assay

[0100] Activity of human recombinant B-Raf protein was assessed in vitroby assay of the incorporation of radiolabelled phosphate to recombinantMAP kinase (MEK), a known physiologic substrate of B-Raf. Catalyticallyactive human recombinant B-Raf protein was obtained by purification fromsf9 insect cells infected with a human B-Raf recombinant baculovirusexpression vector. To ensure that all substrate phosphorylation resultedfrom B-Raf activity, a catalytically inactive form of MEK was utilised.This protein was purified from bacterial cells expression mutantinactive MEK as a fusion protein with glutathione-S-transferase(GST-kdMEK).

[0101] Method: Standard assay conditions of B-Raf catalytic activityutilised 3 ug of GST-kdMEK, 10 uM ATP and 2uCi ³³P-ATP, 50 mM MOPS, 0.1mM EDTA, 0.1M sucrose, 10 mM MgCl₂ plus 0.1% dimethylsulphoxide(containing compound where appropriate) in a total reaction volume of 30ul. Reactions were incubated at 25° C. for 90 minutes and reactionsterminated by addition of EDTA to a final concentration of 50 uM. 10 ulof reaction was spotted to P30 phosphocellulose paper and air dried.Following four washes in ice cold 10% trichloroacetic acid, 0.5%phosphoric acid, papers were air dried prior to addition of liquidscintillant and measurement of radioactvity in a scintillation counter.

[0102] Results: The compounds of the examples were found to be effectivein inhibiting B-Raf mediated phosphorylation of GST-kdMEK substratehaving IC₅₀'s of<3 μM.

[0103] The activity of compounds as Raf inhibitors may also bedetermined by the assays described in WO 99/10325; McDonald, O. B.,Chen, W. J., Ellis, B., Hoffman, C., Overton, L., Rink, M., Smith, A.,Marshall, C. J. and Wood, E. R. (1999) A scintillation proximity assayfor the Raf/MEK/ERK kinase cascade: high throughput screening andidentification of selective enzyme inhibitors, Anal. Biochem. 268:318-329 and AACR meeting New Orleans 1998 Poster 3793.

[0104] The neuroprotective properties of B-Raf inhibitors may bedetermined by the following in vitro assay:

[0105] Neuroprotective properties of B-Raf inhibitors in rat hippocampalslice cultures

[0106] Organotypic cultures provide an intermediate between dissociatedneuronal cell cultures and in-vivo models of oxygen and glucosedeprivation (OGD). The majority of glial-neuronal interactions andneuronal circuitry are maintained in cultured hippocampal slices, sofacilitating investigation of the patterns of death among differing celltypes in a model that resembles the in vivo situation. These culturesallow the study of delayed cellular damage and death 24 hours, or more,post-insult and permit assessment of the consequences of long-termalterations in culture conditions. A number of laboratories havereported delayed neuronal damage in response to OGD in organotypiccultures of the hippocampus (Vornov et al., Stroke, 1994, 25, 57-465;Newell et al., Brain Res., 1995, 676, 38-44). Several classes ofcompounds have been shown to protect in this model, including EAAantagonists (Strasser et al., Brain Res., 1995, 687, 167-174), Nachannel blockers (Tasker et al., J. Neurosci., 1992, 12, 98-4308) and Cachannel blockers (Pringle et al., Stroke, 1996, 7, 2124-2130). To date,relatively little is known of the roles of intracellular kinase mediatedsignalling pathways in neuronal cell death in this model.

[0107] Method: Organotypic hippocampal slice cultures were preparedusing the method of Stoppini et al., J. Neurosci. Methods, 1995, 37,173-182. Briefly, 400 micron sections prepared from hippocampi of 7-8day postnatal Sprague Dawley rats are cultured on semiporous membranesfor 9-12 days. OGD is then induced by incubation in serum andglucose-free medium in an anaerobic chamber for 45 minutes. Cultures arethen returned to the air/CO₂ incubator for 23 hours before analysis.Propidium iodide (PI) is used as an indicator of cell death. PI is nontoxic to neurones and has been used in many studies to ascertain cellviability. In damaged neurons PI enters and binds to nucleic acids.Bound PI shows increased emission at 635 nm when excited at 540 nm. OnePI fluorescence image and one white light image are taken and theproportion of cell death analysed. The area of region CA1 is definedfrom the white light image and superimposed over the PI image. The PIsignal is thresholded and area of PI damage expressed as a percentage ofthe CA1 area. Correlation between PI fluorescence and histologicallyconfirmed cell death has been validated previously by Nissl-stainingusing cresyl fast violet (Newell et al., J. Neurosci., 1995, 15,7702-7711).

[0108] Throughout the specification and the claims which follow, unlessthe context requires otherwise, the word ‘comprise’, and variations suchas ‘comprises’ and ‘comprising’, will be understood to imply theinclusion of a stated integer or step or group of integers but not tothe exclusion of any other integer or step or group of integers orsteps.

1. A compound of formula (I):

wherein X is O, CH₂, S or NH, or the moiety X—R¹ is hydrogen; V is CH orN; R¹ is hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, arylC₁₋₆alkyl,heterocyclyl, heterocyclylC₁₋₆alkyl, heteroaryl, or heteroarylC₁₋₆allylany of which except for hydrogen may be optionally substituted; R² andR³ independently represent optionally substituted C₁₋₆alkyl, or R² andR³ together with the carbon atom to which they are attached form anoptionally substituted C₃₋₇cycloalkyl or C₃₋₇cycloalkenyl ring, or R²and R³ together with the carbon atom to which they are attached form anoptionally substituted 5 to 7-membered heterocyclyl ring containing upto 3 heteroatoms selected from N, O, and S; R⁴ and R⁵ independentlyrepresent hydrogen, C₁₋₆alkyl, C₃₋₇cycloalkyl, aryl, arylC₁₋₆alkyl,heteroaryl, heteroarylC₁₋₆alkyl, heterocyclyl, or heterocyclylC₁₋₆alkyl,any of which, except for hydrogen, may be optionally substituted, or R⁴and R⁵ together with the nitrogen atom to which they are attached form4- to 8-membered ring; Ar is an aryl or heteroaryl ring either of whichmay be optionally substituted; one of X₁ and X₂ is N and the other isNR⁶, wherein R⁶ is hydrogen, C₁₋₆alkyl, or arylC₁₋₆alkyl; or apharmaceutically acceptable salt thereof.
 2. A compound according toclaim 1 wherein X—R¹ is hydrogen.
 3. A compound according to any one ofthe preceding claims wherein Ar is phenyl.
 4. A compound according toclaim 3 wherein Ar is substituted by up to 3 substituents independentlyselected from halo, hydroxy, hydroxy C₁₋₆alkyl, hydroxyimino C₁₋₆alkyl,and C₁₋₆alkoxy.
 5. A compound as claimed in any preceding claim whereinR² and R³ represent C₁₋₆alkyl, or R² and R³ together with the carbonatom to which they are attached form an optionally substitutedC₃₋₇cycloalkyl ring.
 6. A compound as claimed in any preceding claimwherein R⁴ and R⁵ are independently hydrogen, C₁₋₆alkyl, arylC₁₋₆alkyl,C₁₋₇cycloalkyl any of which except hydrogen may be optionallysubstituted, or R⁴ and R⁵ together with the nitrogen to which they areattached form an optionally substituted 5 or 6 membered ring optionallycontaining up to 2 heteroatoms selected from N or O.
 7. A compound asdescribed in the Examples.
 8. A pharmaceutical composition comprising acompound according to any one of claims 1 to 7 or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier. 9.The use of a compound according to any one of claims 1 to 7 or apharmaceutically acceptable salt thereof in the manufacture of amedicament for the prophylactic or therapeutic treatment of any diseasestate in a human, or other mammal, which is exacerbated or caused by aneurotraumatic event.
 10. The use of a compound according to any one ofclaims 1 to 7 or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the prophylactic or therapeutictreatment of cancer.
 11. A compound of formula (II):

wherein X, V, R¹, R², R³, Ar, X₁ and X₂ are as defined for formula (I)and R is hydrogen, C₁₋₆alkyl or arylC₁₋₆alkyl.